Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies.

Abstract

Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies.

• Authors: Éva M Szegő, Antonio Dominguez-Meijide, Ellen Gerhardt, Annekatrin König, David J Koss, Wen Li, Raquel Pinho, Christiane Fahlbusch, Mary Johnson, Patricia Santos, Anna Villar-Piqué, Tobias Thom, Silvio Rizzoli, Matthias Schmitz, Jiayi Li, Inga Zerr, Johannes Attems, Olaf Jahn, Tiago F Outeiro
• Journal: Cell reports (Cell Rep) Vol. 28 Issue 1 Pg. 65-77.e6 (07 02 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31269451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Heat-Shock Proteins
• Snca protein, mouse
• alpha-Synuclein

Topics

• Animals
• Heat-Shock Proteins (metabolism)
• Humans
• Mice
• Mitochondria (metabolism)
• Parkinson Disease (genetics)
• Synucleinopathies (pathology)
• alpha-Synuclein (genetics)